Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling

The physiological roles of PD-1 signaling in B-cell and antibody (Ab) responses remain unclear. We report B cell-extrinsic and B cell-intrinsic deficits of humoral immunity in patients and mice deficient in PD-1 signaling. PD-1- and PD-L1-deficient patients have fewer memory B cells and B-cell receptor (BCR) repertoires with less diversity and somatic hypermutation than healthy donors. Consistently, PD-1 knockout (KO) mice have fewer memory B cells and poorer Ab responses than wild-type mice. Human and mouse PD-1 deficiency compromises IL-21 production by CD4+ alpha beta memory T cells in vitro, whereas PD-L1 deficiency does not. Conversely, human PD-1signaling governs the naive B cell-intrinsic response to T-dependent and T-independent stimulation in vitro. Finally, B-cell-specific PD-1 KO prevents the physiological accumulation of memory B cells in mice. Thus, PD-1 signaling governs Ab responses through both B cell-extrinsic (T cell-dependent) and B cell-intrinsic mechanisms in mice and humans.